Gallic acid attenuates pulmonary fibrosis in a mouse model of transverse aortic contraction-induced heart failure

Mitochondrial calcium ([Ca 2+ ] m ) is essential for cardiomyocyte viability, and aberration of [Ca 2+ ] m is known to elicit multiple cardiac stress conditions associated with ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening, all of which can lead to metabolic stress and the loss of dysfunctional mitochondria by aberrant autophagy. Elucidating the regulatory role of m itochondrial c alcium u niporter (MCU)-mediated [Ca 2+ ] m in modulating cardiac mitochondrial bioenergetics and autophagy has high significance and clinical impact for many pathophysiological processes. [Ca 2+ ] m is exquisitely controlled by the inner mitochondrial membrane uniporter, transporters, regulators and exchangers including MCU, MCUR1, EMRE, MICU1, MICU2 and LETM1. Our recently published findings revealed that Mitochondrial Ca 2+ Uniporter Regulator 1 (MCUR1) serves as a scaffold factor for uniporter complex assembly. We found that deletion of MCUR1 impaired [Ca 2+ ] m uptake, mitochondrial Ca 2+ current ( I MCU ) and mitochondrial bioenergetics and is associated with increased autophagy. Our new findings indicate that the impairment of [Ca 2+ ] m uptake exacerbated autophagy following ischemia-reperfusion (I/R) injury. In support of our mouse model, human failing hearts show that MCUR1 protein levels are markedly decreased and autophagy markers are increased, demonstrating a crucial link between [Ca 2+ ] m uptake and autophagy during heart failure. Additionally, our results reveal that either oxidation or disruption of human MCU Cys-97 (in mouse Cys-96; gain-of-function MCU C96A mutant) produces a conformational change within the N terminal β-grasp fold of MCU which promotes higher-order MCU complex assembly and increased I MCU activity and mitochondrial ROS levels. The results of our studies using a novel cardiac-specific MCUR1-KO model and a constitutively active global MCU C96A KI mouse model (CRISPR-Cas9 genome edited) elucidate the regulatory role of [Ca 2+ ] m in cardiac bioenergetics and autophagy during oxidative stress and myocardial infarction. Thus, targeting assembly and the activity of MCU complex will offer a new potential therapeutic target in the treatment of cardiomyopathy and heart failure.

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Abstract P391: Inhalation Of Airborne Particulate Matter Alters Cardiovascular Function Of Alzheimer-prone Mice

Circulation Research ◽

10.1161/res.129.suppl_1.p391 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Devin R O'Piela ◽

Ty A Saldana ◽

David M Aslaner ◽

Matthew W Gorr ◽

Amy R Mackos ◽

...

Keyword(s):

Heart Failure ◽

Air Pollution ◽

Risk Factor ◽

Particulate Matter ◽

Mouse Model ◽

Transgenic Mouse ◽

Airborne Particulate Matter ◽

Transgenic Mouse Model ◽

Cardiovascular Dysfunction ◽

Airborne Particulate

Air pollution has detrimental effects on cardiovascular and lung function, and the extent of its pathological consequences continues to be uncovered. Recently, air pollution has been implicated in the development of Alzheimer Disease (AD) progression. AD and heart failure are common co-morbidities, giving reason to believe that cardiovascular dysfunction may contribute to AD. A known contributor to cardiovascular dysfunction-particulate matter (PM 2.5 , < 2.5 μm diameter)—is a critical component of air pollution and is considered a risk factor for heart failure and AD development. This co-morbidity pattern and shared environmental risk factor prompted the hypothesis that PM 2.5 contributes to cardiovascular dysfunction in a transgenic mouse model of AD. We tested our hypothesis by subjecting 6-month-old transgenic (APP) and non-carrier wildtype (WT) male mice to filtered air (FA) or PM 2.5 for 5 days/week, 6 hours/day for 3 months (n = 34). Following exposure, echocardiography, pressure-volume (PV) loops, and respiratory mechanics were performed to detect cardiac and pulmonary changes associated with genotype and exposure conditions among the 3-month group. Echocardiography revealed left ventricular anterior wall thickness in systole was significantly elevated among PM-exposed APP mice compared to FA-exposed APP controls. PV data demonstrated significant reduced end-systolic elastance in PM-exposed mice compared to FA-exposed mice in both WT and APP mouse models, demonstrating impaired contractility. PV loops also showed that the time constant of isovolumetric relaxation was increased in PM-exposed compared to FA-exposed WT mice. APP mice experienced higher lung resistance and central airway resistance with an increasing dose of methacholine. Taken together, these findings indicate airborne particulate matter exposure causes cardiac and pulmonary dysfunction in a transgenic mouse model of AD.

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Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.130.suppl_2.16485 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Rebecca H Ritchie ◽

Nga Cao ◽

Yung George Wong ◽

Sarah Rosli ◽

Helen Kiriazis ◽

...

Keyword(s):

Heart Failure ◽

Mouse Model ◽

Diastolic Dysfunction ◽

Diabetic Cardiomyopathy ◽

Ex Vivo ◽

Systolic Function ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Lv Diastolic Dysfunction ◽

The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

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Amelioration of bleomycin-induced pulmonary fibrosis in a mouse model by a combination therapy of bosentan and imatinib

Experimental Lung Research ◽

10.3109/01902148.2014.939312 ◽

2015 ◽

Vol 41 (4) ◽

pp. 173-188 ◽

Cited By ~ 7

Author(s):

Shanmuga Reddy Chilakapati ◽

Mamatha Serasanambati ◽

Prabhakar Vissavajjhala ◽

Jagadeeshwara Reddy Kanala ◽

Damodar Reddy Chilakapati

Keyword(s):

Pulmonary Fibrosis ◽

Combination Therapy ◽

Mouse Model

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Cardioprotective Effects of SIRT6 in a Mouse Model of Transverse Aortic Constriction-Induced Heart Failure

Frontiers in Physiology ◽

10.3389/fphys.2017.00394 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 13

Author(s):

Yongming Li ◽

Xianda Meng ◽

Wenguang Wang ◽

Fu Liu ◽

Zhiru Hao ◽

...

Keyword(s):

Heart Failure ◽

Mouse Model ◽

Transverse Aortic Constriction ◽

Aortic Constriction ◽

Cardioprotective Effects

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Chronic xanthine oxidase inhibition prevents myofibrillar protein oxidation and preserves cardiac function in a transgenic mouse model of cardiomyopathy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00168.2005 ◽

2005 ◽

Vol 289 (4) ◽

pp. H1512-H1518 ◽

Cited By ~ 38

Author(s):

Jennifer G. Duncan ◽

Rajashree Ravi ◽

Linda B. Stull ◽

Anne M. Murphy

Keyword(s):

Heart Failure ◽

Mouse Model ◽

Transgenic Mice ◽

Dilated Cardiomyopathy ◽

Xanthine Oxidase ◽

Protein Oxidation ◽

Oxidase Activity ◽

Myofibrillar Protein ◽

Ventricular Dilation ◽

Xanthine Oxidase Activity

Heart failure is a clinical syndrome associated with elevated levels of oxygen-derived free radicals. Xanthine oxidase activity is believed to be one source of reactive oxygen species in the failing heart. Interventions designed to reduce oxidative stress are believed to have significant therapeutic potential in heart failure. This study tested the hypothesis that xanthine oxidase activity would be elevated in a mouse model of dilated cardiomyopathy and evaluated the effect of chronic oral allopurinol, an inhibitor of xanthine oxidase, on contractility and progressive ventricular dilation in these mice. Nontransgenic and transgenic mice containing a troponin I truncation were treated with oral allopurinol from 2–4 mo of age. Myocardial xanthine oxidase activity was threefold higher in untreated transgenic mice compared with nontransgenic mice. Analyses of myofilament proteins for modification of carbonyl groups demonstrated myofibrillar protein damage in untreated transgenic mice. Treatment with allopurinol for 2 mo suppressed xanthine oxidase activity and myofibrillar protein oxidation. Allopurinol treatment also alleviated ventricular dilation and preserved shortening fraction in the transgenic animals. In addition, cardiac muscle twitch tension was preserved to 70% of nontransgenic levels in allopurinol-treated transgenic mice, a significant improvement over untreated transgenic mice. These findings indicate that chronic inhibition of xanthine oxidase can alter the progression of heart failure in dilated cardiomyopathy.

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Protective Effect of Arbidol Against Pulmonary Fibrosis and Sepsis in Mice

Frontiers in Pharmacology ◽

10.3389/fphar.2020.607075 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hailong Li ◽

Rui Liu ◽

Ruotong Zhang ◽

Shanshan Zhang ◽

Yiying Wei ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Mouse Model ◽

Antiviral Drug ◽

Dynamic Compliance ◽

Serum Levels ◽

Inflammatory Factors ◽

Cytokine Storm ◽

Viral Immunology ◽

Sepsis Induction ◽

Sepsis Score

From the perspective of epidemiology, viral immunology and current clinical research, pulmonary fibrosis may become one of the complications of patients with Coronavirus Disease 2019 (COVID-19). Cytokine storm is a major cause of new coronavirus death. The purpose of this study was to explore the effects of antiviral drug arbidol on cytokine storm and pulmonary fibrosis. Here, we use a mouse model of bleomycin-induced pulmonary fibrosis and a mouse model of fecal dilution-induced sepsis to evaluate the effects of arbidol on pulmonary fibrosis and cytokine storm. The results showed that arbidol significantly reduced the area of pulmonary fibrosis and improved lung function (reduced inspiratory resistance, lung dynamic compliance and forced vital capacity increased). Treatment with arbidol promoted reduced sepsis severity 48 h after sepsis induction, based on weight, murine sepsis score and survival rate. Arbidol observably alleviates inflammatory infiltrates and injury in the lungs and liver. Finally, we also found that arbidol reduced serum levels of pro-inflammatory factors such as TNF-α and IL-6 induced by fecal dilution. In conclusion, our results indicate that arbidol can alleviate the severity of pulmonary fibrosis and sepsis, and provide some reference for the treatment of cytokine storm and sequelae of pulmonary fibrosis in patients with COVID-19.

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